Type 1 diabetes (T1D) is a chronic autoimmune disease resulting in loss of pancreatic -cells and insulin secretion. Attempts to suppress autoimmunity and preserve -cells have returned modest clinical efficacy, both in magnitude and duration. Many trials involved generalized immunosuppression and/or depletion of various immune cell types, or short course therapies, which may not afford sustained benefit given the chronic nature of islet autoimmunity; yet chronic immunosuppression is limited by safety concerns. There is a need for therapies that afford immunomodulation and can be given chronically with high margins of safety to treat islet autoimmunity. It is important to develop therapies with antigen specificity, for enhanced safety, potency and disease relevance. The cytokine Interleukin-2 (IL-2) is essential for effector T cell responses, but also for regulatory T (Treg) cells that are key to self-tolerance. Clinical trials with low-dose IL-2 conducted in several immune-mediated diseases report significant clinical benefit associated with enhanced Treg function, with an excellent safety profile. We have shown that human CD4 Treg cells have heightened sensitivity to low-dose IL- 2 compared to effector T cells (Teff), in vitro, and uncovered some of the mechanisms by which IL-2 could promote Treg function and immune regulation when given at low doses to patients with T1D, as observed in the first T1D trial, which was not designed to did not test effects on insulin secretion. We now propose a multicenter clinical trial to investigate low-dose IL-2 as a therapeutic agent in T1D and its mechanisms of action. We will enroll 12-21 year-old patients with established T1D (4-12 months duration); most patients meet C-peptide eligibility criteria for at least 2 years following diagnosis and demonstrating benefit in this population would impact the field by expanding the therapeutic window. Participants will be randomized to placebo for 2 years, or low-dose IL-2 therapy for either 1 or 2 years. The primary hypothesis is that low-dose IL-2 therapy will be safe, will preserve insulin secretion and increase Treg proportions. This trial will exploit the fact that T1D requires multiple insulin injections daily and thus patients immunize themselves with a key T1D autoantigen. We hypothesize that insulin therapy synergizes with low-dose IL-2 by inducing insulin-specific Treg cells. This result would support exploiting IL-2 in combination with antigen(s) to promote antigen/disease specific immune regulation in autoimmune disease. The study has three specific aims: Aim 1: To determine the efficacy and safety of low-dose IL-2 therapy in patients with established T1D. The primary clinical and mechanistic objectives are the efficacy of low-dose IL-2 in preserving insulin secretion and improving proportions of Treg cells, compared to placebo. Aim 2: To identify mechanisms and biomarkers of response in T1D patients undergoing low-dose IL-2 therapy through the study of immune homeostasis, IL-2R signaling, gene expression, and T cell metabolism. Aim 3. To evaluate the ability of low-dose IL-2 therapy to reduce autoreactive CD4 and CD8 T cells and increase insulin-specific Tregs. These data will be related to effects of the therapy on serum cytokine levels and the TCR repertoires.